Multipole ion guide for mass spectrometry

ABSTRACT

A multipole ion guide which begins in one pumping stage and extends continuously into one or more subsequent pumping stages has been incorporated into an atmospheric pressure ion source mass spectrometer system. Ions delivered into vacuum from an Electrospray, Atmospheric Pressure Chemical Ionization or Inductively Coupled Plasma ion source are guided and focused into a mass analyzer with high efficiency using the multipole ion guide. The background pressure over a portion of the multipole ion guide length is high enough to cause kinetic energy cooling of ions traversing the ion guide length due to ion collisions with neutral background gas molecules. This ion kinetic energy cooling lowers energy spread of ions traversing the multipole ion guide length. The multipole ion guide DC offset potential can be used to adjust the mean ion energy and the ion guide a n  and q n  values can be set to reduce or expand the range of ion mass to charge which will be transmitted through the ion guide. These features of multipole ion guides and multiple pumping stage multipole ion guides are used to improve performance and lower the cost of Atmospheric Pressure Ion source mass spectrometer instruments.

RELATED APPLICATIONS

The present application is a continuation of U.S. Nonprovisional patentapplication Ser. No. 09/373,337 filed Aug. 12, 1999 now U.S. Pat. No.6,188,066 which is a continuation of U.S. Nonprovisional patentapplication Ser. No. 08/794,970 filed Feb. 5, 1997 (patented as U.S.Pat. No. 5,962,851 issued on Oct. 5, 1999), which is a continuation ofU.S. Nonprovisional patent application Ser. No. 08/645,826 filed May 14,1996 (patented as U.S. Pat. No. 5,652,427 issued on Jul. 29, 1997),which is a continuation of U.S. Nonprovisional patent applicaition Ser.No. 08/202,505 filed Feb. 28, 1994 (abandoned). This application claimsall rights of priority to those prior applications, and all of thoseprior applications are fully incorporated herein by reference.

FIELD OF INVENTION

This invention relates to the configuration and method of using amultipole ion guide to transport and focus ions which enter vacuum froman atmospheric pressure ion source, into a mass analyzer. The multipoleon guide which begins in one vacuum pumping stage has been configured toextend contiguously through one or more subsequent vacuum stages.Multipole ion guides are used to efficiently transfer ions through oneor more vacuum stages while allowing the neutral background gas to bepumped away. The AC frequency and AC and DC voltages which are appliedto the poles of a multipole ion guide can be set so that the multipoleion guide will pass a selected range of ion mass to charge. The iontransmission properties of multipole ion guides can be used to enhanceperformance of specific mass analyzer types which are interfaced toatmospheric pressure ion sources.

BACKGROUND OF THE INVENTION

Atmospheric pressure ion sources (API) have become increasinglyimportant as a means for generating ions used in mass analysis.Electrospray or nebulization assisted Electrospray (ES), AtmosphericPressure Chemical Ionization (APCI) and Inductively Coupled Plasma (ICP)ion sources produce ions from analyte species in a region which isapproximately at atmospheric pressure. The ions must then be transportedinto vacuum for mass analysis. A portion of the ions created in the APIsource are entrained in the bath gas API source chamber and are sweptinto vacuum along with a the bath or carrier gas through an orifice intovacuum. Mass spectrometers (MS) generally operate in a vacuum maintainedat between 10⁻⁴ to 10⁻¹⁰ torr depending on the mass analyzer type. Thegas phase ions entering vacuum from an API source must be separated fromthe background carrier gas and transported and focused through a singleor multiple staged vacuum system into the mass analyzer. Variations invacuum system and associated electrostatic lens configurations haveemerged in API/MS systems. Where multiple pumping stages have beenemployed, the electrostatic lens elements have been configured to serveas restricted orifices between vacuum stages as well as providing ionacceleration and focusing of ion into the mass analyzer. Performancetradeoffs may occur where electrostatic lenses must also accommodaterestricting the neutral gas transmission from one pumping stage to thenext. For example, a skimmer placed between one pumping stage and thenext may restrict the neutral gas flow but may also restrict the passageof ions as well due to its relatively small orifice. Two types ofElectrostatic elements have been used to transport and focus ions invacuum, particularly where ions are entering vacuum from atmosphericpressure through a free jet expansion. The first is a static voltagelens and the second is a dynamic field ion guide. The most effectivelens configurations used in API/MS systems employ a judiciouscombination of both elements which have static and dynamic fieldsapplied.

The first electrostatic lens type has a fixed or static DC voltageapplied during the time an ion is traversing the lenses' field. FIG. 1is a diagrammatic representation of a four pumping stage API/MS systemwith static voltage electrostatic lenses. Gas emerging from thecapillary exit 8 into vacuum expands as a supersonic free jet and aportion of the gas passes through the first 10 and second 14 skimmer.Skimmers between pumping stages typically have small orifices torestrict the neutral gas flow into each downstream vacuum stage. DCvoltages are applied to the capillary exit, skimmers and otherelectrostatic lenses 9, 14, 15, 16 and 17 with values set to maximizethe ion transmission into the mass spectrometer. Ions entrained in theexpanding gas follow trajectories that are driven by a combination ofelectrostatic and gas dynamic forces. Strong influence from the gasdynamics can extend up to and beyond the second skimmer 13 for theconfiguration shown in Figure one. The efficiency of ion transmissionthrough a static voltage lens set can be reduced by scattering lossesdue to collisions between ions and the background gas which occur alongthe ion trajectory. Ions with different m/z may vary their collisionalcross sections and hence experience different numbers of backgroundcollisions as they are transported through vacuum. For a givenelectrostatic lens voltage setting the efficiency of ion transport intothe mass spectrometer may vary with m/z or the collisional crosssection. Changing the lens voltage values may optimize transmission fora given ion species but the setting may not be optimal for another ionspecies transmission. For example static lens configurations used inAPI/MS applications may not transmit lower molecular mass compounds asefficiently as higher molecular mass compounds. The smaller ions maysustain higher transmission losses due to collisional scattering fromthe background gas than the higher molecular mass compounds. To increaseion transmission efficiency through a static lens stack, theelectrostatic energy must be set sufficiently high so that ions can bedriven through the background gas. Static voltage lens configurationsalso tend to focus ions of different energy at different focal points.If the focal point is not located at the mass spectrometer entrancetransmission losses can occur. To overcome the mass to chargetransmission discrimination effects and ion transport inefficiencieswhich occur when static voltage lenses are used, multipole dynamic fieldion guides have been employed to transport ions through vacuum pumpingstages in the vacuum region of API/MS systems. The dynamic electrostaticfields within a multipole ion guide dominate over the background gasscattering collisions and effectively “trap” the ions while theytraverse the length of the multipole ion guide.

The use of multipole ion guides has been shown to be an effective meansof transporting ions through vacuum. Publications by Olivers et. al.(Anal. Chem, Vol. 59, p. 1230-1232, 1987), Smith et. al. (Anal. Chem.Vol. 60, p.436-441, 1988) and U.S. Pat. No. 4,963,736 (1990) havereported the use of a quadrupole ion guide operated in the AC-only modeto transport ions from an API source into a quadrupole mass analyzer.U.S. Pat. No. 4,963,736 describes the use of a multipole ion guide ineither vacuum pumping stage two of a three stage system or in the firstpumping stage of a two stage vacuum system. This patent also reportsthat increasing the background pressure up to 10 millitorr in the vacuumstage where the ion guide was positioned resulted in an increase in iontransmission efficiency and a decrease in ion energy spread of ionstransmitted. Ion signal intensity decreased for higher backgroundpressures in the reported quadrupole configuration. A commerciallyavailable API/MS instrument manufactured by Sciex, a Canadian company,incorporates a quadrupole ion guide operated in the AC-only mode locatedbefore the quadruple mass filter in a single stage vacuum system. Ionsand neutral gas flowing into vacuum through an orifice in the API sourceenter the quadrupole AC-only ion guide. The ions are trapped fromexpanding in the radial direction by the AC quadrupole fields and aretransmitted along the quadrupole ion guide rod length as the neutral gasis pumped away through the rod spacing. Ions exiting the quadrupole ionguide are focused into a quadrupole mass filter located in the samevacuum chamber. Neutral gas is pumped away by a high capacity andrelatively expensive cyro pump. Multiple quadrupole ion guides have beenused to transport ions from API sources through multiple vacuum pumpingstages and into a Fourier-Transform Ion Cyclotron Resonance massanalyzer. Beu et. al. (J. Am. Soc. Mass Spectrom vol. 4. 546-556, 1993)have reported using three quadrupole ion guides operated in the AC-onlymode located in three consecutive vacuum pumping stages of a fivepumping stage Electrospray Fourier-Transform Ion Cyclotron Resonance(FT-ICR) mass spectrometer instrument. The multiple pumping stages arerequired to achieve operating pressures in the mass analyzer of lessthan 2×10⁻⁹ torr. Orifices mounted in the partitions between each vacuumpumping stage which restricted neutral gas conductance from one pumpingstage to the next were located between consecutive quadrupole ionguides.

Over the past few years as API/MS system design has evolved, higherperformance with lower system cost has been achieved by using multiplevacuum stages to remove the background gas from the ions which enterfrom atmospheric pressure into vacuum. The type of mass analyzer towhich an API source is interfaced places its unique demands on the iontransport lens configurations and vacuum requirements in the iontransport region between atmospheric pressure and the mass analyzer.Each mass analyzer type has an acceptable ion energy, ion energy spreadand entrance angular divergence which the upstream ion transport lenssystem must satisfy when delivering ions to the entrance of a massspectrometer. For example, a quadrupole mass analyzer can accept ionswith axial translational energy generally below 40 electron voltswhereas a magnetic sector mass spectrometer requires ions with thousandsof volts of axial translational energy.

In the present invention, a multipole ion guide is configured toincrease the overall sensitivity of an API/MS system while reducinginstrument cost and complexity. In one embodiment of the presentinvention, a multipole ion guide is used to transport ions enteringvacuum from an API source to non-dispersion type mass analyzers. A rangeof ion mass to charge (m/z) can be efficiently transmitted through amultipole ion guide provided the ion guide operating stability region isset to pass those values of m/z. If an ion with a given mass to chargeratio falls within the operating stability region set for a multipoleion guide, the ion will be effectively trapped from drifting to far inthe off axis direction but is free to move in the direction of ion guideaxis. If the ion m/z falls outside the stability region, it will nothave a stable trajectory and will be rejected from the ion guide beforeit reaches the exit end. Collisions between an ion and the backgroundgas within the multipole assembly can also effect the ion trajectory andthe ion kinetic energy as it passes through the multipole ion guide. Thebackground gas, if present at high enough pressure, may serve, throughcollisions, to damp the motion of ions as they pass through themultipole ion guide, cooling their kinetic and thermal energy. This aidsin forming an ion beam which exits the multipole ion guide with reducedenergy spread for a given ion species within the beam. The range of m/zwhich are transmitted through a multipole ion guide for a givenbackground pressure environment can be varied by adjusting the ACfrequency and AC and/or a DC voltage which can be applied with alternatepolarity to each adjacent rod. The offset potential of the multipolelens, that is the DC voltage applied uniformly to all the rods on whichthe AC and alternate polarity DC rod potentials are floated andreferenced is one variable that can to be used to set the energy of ionstransmitted through the multipole ion guide. Multipole ion guides can beconfigured to efficiently transport ions through a wide range of vacuumpressures. The ability of a multipole ion guide to deliver and ion beamwith low energy spread and where the mean energy and m/z range can beadjusted into a mass analyzer can be used to improve the performance ofan API/Time-Of-Flight, API/Ion Trap and API/FT-ICR mass spectrometersystems.

Another embodiment of the invention is the incorporation of a multiplevacuum pumping stage multipole ion guide into an API/MS system. Amultiple vacuum pumping stage multipole ion guide is a multipole ionguide which begins in one pumping stage and extends contiguously throughone or more additional vacuum pumping stages of a multiple pumping stagesystem. Multipole ion guides which are located in only one vacuumpumping stage of a multiple pumping stage system must deliver the ionsexiting the ion guide into an aperture with static voltage applied. Ifbackground pressure is high enough to scatter the ions after themultipole ion guide exit or the aperture to the next pumping stage has asmaller diameter than the ion beam cross section, losses in iontransmission can occur. If individual multipole ion guides are locatedprogressively in the first few pumping stages of an API/MS system, iontransmission losses can occur when transferring ions between pumpingstages. If fewer pumping stages are used to reduce the ion transmissionlosses between pumping stages, the total gas flow and hence the totalnumber of ions which can be delivered to vacuum may be compromised. Over95% ion transmission efficiency can be achieved through multiple vacuumpumping stages using multipole ion guides configured to extendcontiguously through two or more vacuum pumping stages. A multiplevacuum stage multipole ion guide must be configured serve as an ionguide with an internal open area small enough to minimize the neutralgas flow from one pumping stage to the next. Xu at. el. (Nuclear Instr.and Methods in Physics Research, Vol. 333, p. 274, 1993) have developeda hexapole lens which extends through two vacuum pumping stages totransport ions formed in a helium discharge source operated in a chambermaintained at 75 to 150 torr of pressure through two vacuum pumpingstages into a faraday cup detector. The discharge ion source deliveredions into a two stage vacuum system through an orifice in the end wallof the source chamber. The background pressure in the first vacuumpumping stage was 600 millitorr and the second vacuum stage backgroundpressure was 98 millitorr. Ion transmission efficiencies through thehexapole ion guide beginning in vacuum stage one and extending unbrokeninto vacuum stage two approached 90% for O₂ ⁺. The helium discharge ionsource background pressure in this apparatus was 5 to 10 times belowatmospheric pressure and helium was used as the background gas.Different configuration and performance criteria exist for multiplepumping stage multipole ions guides incorporated into an API/MS systemthan were required for the ion guide application described by Xu andcoworkers. Multipole ion guides incorporated into API/MS systems musthave the capability of efficiently transmitting ions of various chargestates over a wide range of mass to charge. Nitrogen, not helium, istypically used as carrier gas in API sources and the backgroundpressures in API/MS multiple vacuum stage systems are often widelydifferent from the pressures reported in the ion guide apparatusreported by Xu. An added constraint imposed on API/MS systems which wasnot present in the non API/MS application practiced by Wu et. al. is theability to fragment molecular ions by Collisional Induced Dissociation(CID) in the gas expansion region in the first two vacuum stages.Valuable structural information can be obtained from CID of molecularions produced in ES and APCI sources. CID conditions can be set byadjusting relative potentials between static voltage lenses and even theDC offset potentials of multipole ion guides located in the first twovacuum pumping stages of a API source.

In the present invention, multiple pumping stage multipole ion guidesare configured to maximize performance of API/MS systems while reducingsystem vacuum pump cost. Increasing signal sensitivity while loweringvacuum pumping cost is achieved by maximizing the ion transferefficiency from the API source into the mass analyzer while minimizingthe amount of neutral gas transferred. For the multiple pumping stagemultipole ion guides which begin in one vacuum pumping stage and extendthrough one or more subsequent pumping stages, the rod diameter and rodspacing in the multipole ion guide assembly were configured small enoughto minimize the transmission of neutral gas through the ion guide intodownstream pumping stages. Acceptable vacuum pressure per pumping stagewas be achieved with moderate capacity vacuum pumps. The ion guide witha small inner diameter was configured to allow sufficient conduction ofneutral gas through the spaces between the rods or poles so the neutralgas was pumped away efficiently in each pumping stage. The smallmultipole ion guide inner diameter produced an ion beam with aproportionally small cross section. The smaller cross section ion beamfocused into the mass analyzer allowed the reduction of the massanalyzer entrance aperture without compromising ion transmissionefficiency. Efficient ion transport, better control of ion energy andenergy spread and a small beam diameter is achieved by using a multiplevacuum pumping stage multipole ion guide.

SUMMARY OF THE INVENTION

In accordance with the present invention, an Atmospheric Pressure Ionsource which includes Electrospray or nebulization assistedElectrospray, Atmospheric Pressure Chemical Ionization and InductivelyCoupled Plasma ion sources interfaced to a mass analyzer incorporates amultipole ion guide in the vacuum pumping region between the API sourceand the mass analyzer.

In one embodiment of the invention, the API/MS system includes multiplevacuum pumping stages and a multipole ion guide which begins in onevacuum pumping stage and extends contiguously through two or more vacuumpumping stages. The multipole ion guide inner diameter is reduced tominimize the neutral gas conduction between vacuum pumping stages whileallowing the efficient transport of ions through the multipole ion guidelength. At least one portion of a multiple vacuum stage multipole ionguide is subject to background gas pressures which are high enough thatthe ions traversing the ion guide length are subject to many collisionswith neutral background gas molecules. Ion transmission efficienciesthrough such multipole ion guide assemblies can exceed 95% even withbackground pressures in a given vacuum pumping stage of hundreds ofmillitorr. Collisions between the ions and the background neutral was inthe multipole ion guide cause cooling of the ion kinetic energy,reducing the ion energy spread. The AC field of the multipole ion guidetraps ions within a radial cross section and prevents scattering lossesof the ions undergoing collisions with the background gas as the ionstraverse the ion guide length. The energy of the ions exiting themultipole ion guide relative to the mass analyzer entrance aperturepotential can be set by varying the multipole ion guide DC offsetpotential. With sufficient ion kinetic energy cooling in the ion guide,ion energy can be adjusted over a wide range with little change to theion energy spread for a given m/z. Ions with mean energies of a fewelectron volts or lower can be transmitted into the mass analyzerentrance aperture by using multiple vacuum pumping stage multipole ionguides. Lower energy ions with a narrow energy spread transmitted intoquadrupole mass analyzers will result in higher sensitivity for a givenresolution than can be achieved with higher energy ions. Increasedsensitivity and resolution can be achieved by using multiple vacuumpumping stage multipole ion guides with reduced vacuum system costs forquadrupole, time-of-flight, ion trap, FT-ICR and magnetic sector massspectrometers.

When operating multipole ion guides in the AC only mode or with AC andDC applied to the poles, the frequency and voltage levels can be set sothat a broad range of m/z ions will be transmitted through the multipoleion guide. The AC frequency and AC and DC voltages can also be set torestrict the range of m/z values that will be transmitted through themultipole ion guide for a given background pressure environment.Narrowing the range of m/z values transmitted to the analyzer of a TOFmass spectrometer can be used to increase the duty cycle and hencesensitivity of an API/TOF mass spectrometer instrument. Limiting therange of m/z for ions transmitted into an ion trap or the analyzer cellof an FT-ICR mass spectrometer instrument can reduce the effects ofspace charging in the trap or FT-ICR cell during mass analysis. This canimprove the mass measurement accuracy, resolution and dynamic range ofthe mass analyzer.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram of a four vacuum stage ES/MS quadrupole instrumentwith a static lens configuration incorporated into vacuum stages 1through 3.

FIG. 2 is a diagram of a four vacuum stage ES/MS quadrupole instrumentwith a multipole ion guide beginning in the second vacuum pumping stageand extending contiguously into the third pumping stage.

FIG. 3a shows the transmission efficiency of ions through a two vacuumstage multipole ion guide for m/z 110 over a range of values for q_(n).

FIG. 3b shows the transmission efficiency of ions through a two vacuumstage multipole ion guide for m/z 872 over a range of values for q_(n).

FIG. 3c shows the transmission efficiency of ions through a two vacuumstage multipole ion guide for m/z 1743 over a range of values for q_(n).

FIG. 4 is a mass spectrum of Glucagon with the two vacuum pumping stagemultipole ion guide q_(n) value set to pass a wide range of m/z values.

FIG. 5a is an Electrospray mass spectrum of Arginine where the multipoleion guide q_(n) value is set to pass a broad range of m/z values.

FIG. 5b is a mass spectrum of Arginine where the multipole ion guideq_(n) value is set so that a low m/z cutoff ion transmission occurs.

FIG. 6a is an Electrospray mass spectrum of Gramicidin S where themultipole ion guide q_(n) value is set to pass a broad range of m/zvalues.

FIG. 6b is a mass spectrum of Gramicidin S where the multipole ion guideq_(n) value is set so that a low m/z cutoff ion transmission occurs.

FIG. 7a is an Electrospray mass spectrum of a mixture of Arginine,Leucine Enkephalin and Gramicidin S where the multipole ion guide q_(n)value is set to pass a broad range of m/z values.

FIG. 7b is a mass spectrum of a mixture of Arginine, Leucine Enkephalinand Gramicidin S where the multipole ion guide q_(n) value is set sothat a high m/z cutoff ion transmission occurs.

FIG. 8a is a curve of ion signal for m/z 571 versus the multipole ionguide exit lens potential for a multipole ion guide DC offset potentialset at 0.1 volts.

FIG. 8b is a curve of ion signal for m/z 571 versus the multipole ionguide exit lens potential for a multipole ion guide DC offset potentialset at 15.3 volts.

FIG. 8c is a curve of ion signal for m/z 571 versus the multipole ionguide exit lens potential for a multipole ion guide DC offset potentialset at 25.1 volts.

FIG. 9 is a spectrum of a doubly charged Gramicidin S peak scanned withthe multipole ion guide offset potential set at 0.1 volt.

FIG. 10 is a diagram of a four vacuum stage ES/MS Time-OF-Flightinstrument with orthogonal pulsing including a multipole ion guidebeginning in the second vacuum pumping stage and extending into thethird vacuum pumping stage.

FIG. 11 is a diagram of a three vacuum stage ES/MS ion trap instrumentwith a multipole ion guide beginning in the first vacuum stage andextending through the second and into the third vacuum pumping stages.

FIG. 12 is a cross section of a hexapole ion guide including theelectrically insulating mounting bracket.

FIG. 13 is a diagram of a three vacuum pumping stage API/MS ion trapinstrument with a single pumping stage multipole ion guide located inthe second vacuum stage.

FIG. 14 is a diagram of a four vacuum pumping stage API/orthogonalpulsing TOF mass spectrometer instrument with single vacuum stagemultipole ion guides located in the second and third vacuum stages.

DESCRIPTION OF THE INVENTION

Sample bearing liquid is introduced into atmospheric pressure ionizationsources including ES, APCI and ICP sources and gas phase ions areproduced from the analyte in solution. API/MS systems are availablewhich include from one to over five vacuum pumping stages. AnElectrospray ion source interfaced to a quadrupole mass spectrometer isdiagrammed in FIG. 1. The system shown includes four vacuum pumpingstages and a static voltage lens configuration to transfer ions throughthe first three pumping stages and focus them into the entrance ofquadrupole mass spectrometer 18. In the configuration shown, samplebearing liquid is introduced through needle 1 and is Electrosprayed intothe bath gas in chamber 2. Liquid droplets evaporate in chamber 2 or asthey are swept into vacuum through capillary 3 and ions are releasedfrom the evaporating droplets. The charged liquid droplets can be driedby using a countercurrent drying gas 23 and/or a heated capillary 3. Aportion of the ions and charged droplets formed in electrospray chamber2 enter the capillary entrance 4 along with a portion of the backgroundbath gas and are swept into vacuum through the capillary annulus 5.Alternatively the capillary orifice into vacuum could be replaced by anozzle with appropriate orifice size. The bath or carrier gas andentrained ions are swept through the capillary and enter the firstvacuum stage 7 after passing through the capillary exit 8. The pressurein vacuum stage 7 is generally maintained between 0.4 and 20 torr so thegas exiting the capillary expands in a supersonic free jet. The ionsentrained in this free jet are accelerated by collisions with theexpanding background gas. The background gas used is usually nitrogenbut may be also be carbon dioxide, oxygen, helium or any number of othergases which suit the analysis requirements and ion source type. Anelectrostatic field is applied between the capillary exit 8, the ringlens 9 and the first skimmer 10 to electrostatically focus andaccelerate ions through the skimmer 10 orifice 11 and on into the secondvacuum stage 12. Vacuum stage 12 is typically operated at a pressureranging from 5 to 200 millitorr depending on pumping speeds and the sizeof skimmer orifice 11. Electrostatic potentials are maintained betweenskimmers 10 and 13 and a portion of the ions passing through skimmer 10are focused through orifice 22 in skimmer 13 into the third vacuumpumping stage 20. Pressure in pumping stage 20 is maintained typicallybetween 1×10⁻³ to below 8×10⁻⁵ torr. Potentials are set on electrostaticlens elements 14, 15 and 16 to focus ions through aperture 17 afterwhich they pass into the quadrupole mass filter 18 located in the fourthpumping stage 24.

The static voltage lens system shown in FIG. 1 transmits and focusesions through the vacuum stages and into the mass analyzer while allowingthe background gas to be pumped away. The ion energy relative to thequadrupole mass filter offset voltage is established by a combination ofacceleration energy imparted by the expanding carrier gas and theelectrostatic potentials applied. The capillary exit 8 potentialrelative to the ring electrode 9 and skimmer electrode 10 can be sethigh enough to cause Collisional Induced Dissociation (CID) which canaffect the energy and energy spread of the parent and fragment ions. Iontransmission losses can occur in each pumping stage due to scatteringfrom background pressure and the inability to electrostatically focusions through the pumping stage skimmer orifices 11 and 22 and thequadrupole entrance aperture 17. To achieve the desired pressures perpumping stage while constraining the vacuum pumping speeds to fall below800 L/sec to reduce the vacuum pump cost and size, skimmer orifice 11 inthis configuration would typically have a diameter of 0.8 to 1.5 mm andskimmer orifice 22 may range from 0.8 to 3.0 mm. The smaller the skimmerorifice size the fewer the number of ions that can be transmittedthrough this static lens configuration. The higher the energy spread forions of a given m/z and the larger the energy difference for ions withdifferent m/z, the fewer the ions that can be efficiently focused intothe mass spectrometer and effectively mass analyzed. Depending on vacuumpressures maintained during operation, the static lens configurationshown may exhibit different transmission efficiencies for different m/zvalues. Also, with static voltage lens systems, ion transmissionefficiency drops off rapidly as the ion energy is reduced below 10electron volts.

To improve ion transmission performance yet retain the advantages ofmultiple pumping stages to more cost effectively remove neutral gas, amultipole ion guide has been used, replacing some of the static voltagelenses. FIG. 2 illustrates a multipole lens assembly 40 which begins invacuum pumping stage 41 and extends unbroken into vacuum pumping stage42. Individual rods or poles 45 in assembly 40 are held in place andelectrically isolated from the partition between vacuum pumping stage 41and 42 by insulator 43. A cross section of a hexapole ion guide isillustrated in FIG. 12 with insulator 156 serving the dual purpose ofholding the six rods or poles 160 in position while minimizing theeffective aperture area inside the rods assembly diameter through whichneutral gas flows and ions are transmitted from one pumping stage to thenext. Multipole ion guide assembly 40 consists of parallel electrodes 45in FIG. 12 shown as round rods 160 equally spaced with a common radiusfrom the centerline. An octapole ion guide would have eight equallyspaced rods and a quadrupole would have four equally spaced rods orpoles. When multipole ion guide 40 is operated in the AC-only mode,every other rod has the same AC frequency, voltage and phase and everyadjacent rod has the same AC frequency and voltage applied but a phasedifference of 180 degrees. So for a hexapole ion guide, three rods orpoles would be operated with the same AC frequency, voltage and phaseand the same AC frequency and voltage with a phase difference of 180degrees would be applied to the remaining three rods. A DC offsetvoltage is applied to all rods 45 of the multipole ion guide 40 andplays a large role in establishing the ion energy. The multipole ionguide DC offset potential is set to focus ions passing through skimmer47 orifice 48 into the multipole ion guide. The kinetic energy of theions entering multipole ion guide 40 has contributions from the velocityimparted by the expanding gas exiting capillary exit 50, the relativeelectrostatic DC potentials applied to capillary exit 50, ring lens 51,skimmer 47 and the multipole rod 40 DC offset potential as well as anyAC voltage component from fringing fields as ions enter multipole ionguide 40. Static voltage lens elements may be added at the exit end 52of the multipole ion guide to focus ions into the mass analyzer entrance47. Lens 53 is positioned at exit 52 of multipole ion guide 40 to shieldthe exiting ions from the multipole AC voltage fringing fields and tofocus the ions into the mass analyzer entrance aperture 47. Theefficiency of ion transport through this two pumping stage multipole ionguide 40 is over 95% for a wide range of ion m/z values. Iontransmission efficiencies were determined by measuring the total ioncurrent which passed through skimmer orifice 48 and by measuring thetotal ion current exiting multipole ion guide 40 for the sameelectrospray ion source operating conditions.

The performance characteristics of the two vacuum pumping stagemultipole ion guide 40 diagrammed in FIG. 2 will be used as an examplealthough many variations in multiple pumping stage multipole ion guidesare possible. A hexapole ion guide was configured with rods beginning invacuum pumping stage 41 and extending contiguously into vacuum pumpingstage 42 of a four stage system as diagrammed in FIG. 2. For testingpurposes, the background pressures could be varied in the first andsecond pumping stages 53 and 41. With multipole ion guide 40 operated inthe AC-only mode, the AC frequency and amplitude and the DC offsetpotentials were varied to map out performance over a range of backgroundpressures.

A two vacuum stage hexapole ion guide was chosen over a quadrupole oroctapole because for this four vacuum stage API/MS system because thehexapole configuration was the most favorable compromise betweentrapping efficiency, vacuum pumping conduction through the rod spacingand overlap of stability regions for a wide range of m/z values andbackground pressures. Two non-dimensional coefficients a_(n) and q_(n)are commonly used when mapping ion trajectories in multipole ion guidesor mass filters by solving the Laplace equation of motion. The twocoefficients are defined as:$a_{n} = {{\frac{n^{3}U}{2\left( \frac{m}{z} \right)\omega^{2}r_{O}^{2}}\quad {and}\quad q_{n}} = \frac{n^{3}V}{4\left( \frac{m}{z} \right)\omega^{2}r_{O}^{2}}}$

where n is the number of rod pairs (n=3 for a hexapole), U is the DCpotential applied to the rods, every other rod having opposite polarity,m/z is the mass to charge ratio of the ion traversing the multipole ionguide, co is the frequency applied, V is the zero-to-peak AC potentialapplied to the rods, every other rod being 180 degrees out of phase, andr₀ is the radius from the assembly centerline. When the multipole ionguide is operated in the AC-only mode, U is set equal to zero so a_(n)drops out of the equation of motion. The DC rod offset potential appliedequally to all rods only effects the ion trajectories entering andleaving the multipole ion guide 40. The offset potential should noteffect the stability of the ion trajectories once the ions pass into theion guide and are trapped within the rods other than to influence theirinitial entrance trajectory. For the configuration shown in FIG. 2, thebackground gas pressure inside the rod assembly varies along themultipole ion guide length and will effect the ion trajectories throughthe ion guide. To theoretically model the effect of the backgroundneutral gas collisions on the ion trajectory through a multipole ionguide, the cross section of the ions must be known. The collisionalcross sections of ions generated by API sources are not always known,however. In particular, the cross section of multiply charged ions whichcan be produced in the electrospray ion source are not always known.Consequently, for a given multipole ion guide configuration, values ofa_(n) and q_(n) where efficient ion transmission through the multipolelens can be achieved must be mapped for any given m/z and backgroundpressure combination encountered.

The rod AC voltages were ramped for different radio frequency (RF)values using the multipole ion guide configuration diagrammed in FIG. 2,to map the regions of stable q_(n) for all m/z falling within the rangeof the quadrupole mass spectrometer. The background pressure gradientwas held constant for each set of ion transmission tests to establishthe values of q_(n) where stable and efficient ion trajectories throughthe two vacuum stage multipole ion guide 40 could be achieved. Thenumber of ion to neutral gas collisions that occur as an ion transversesthe rod length is a function of the background pressure as well as therod length. The longer the rods, the more collisions which occur for anion traversing the rods in a given background pressure. The multipoleion guide assembly 40 was constructed with an effective inner diametersmaller than 2.5 millimeters to minimize the neutral gas conductionbetween vacuum stages 41 and 42. The rod length in vacuum stage 41 was2.9 cm and the rod length in stage 42 was 3.0 cm. For this multipole ionguide configuration and background pressure gradient tested, the ACvoltage applied was kept below the point where electrical breakdownoccurred between the rods. To determine which values of q_(n) allow astable trajectory for an ion with a given m/z and charge state, themultipole RF amplitude was ramped for set frequencies ranging from 1 to10 MHz.

An example a test series is given in FIGS. 3a, 3 b and 3 c taken withfollowing background pressures: pumping stage 53 was 2 torr, pumpingstage 41, 150 millitorr, pumping stage 42, 4×10⁻⁴ torr and pumping stage54 was 6×10⁻⁶ torr. For the data taken in FIG. 3a, the quadrupole massfilter was scanned from m/z 109.6 to 110.6. The ion signal was measuredat each 1 MHz step of the RF frequency varying the RF amplitude to findthe maximum signal. At each RF frequency the RF amplitude was rampedfrom minimum to maximum and then ramped back to its minimum value. Atpoint 61 in FIG. 3a the two vacuum stage multipole ion guide is beingoperated in the AC-only mode with its RF frequency set at 3 MHz and theRF amplitude set low. As the RF amplitude is ramped to its maximum valueat 62, the ion transmission efficiency reaches its maximum at 63 forthis frequency and m/z. From 62 the amplitude is ramped down to itsoriginal low value at 64 where little or no ion transmission isobserved. The signal maximum observed at 65 has the same RF amplitude asat 63 as expected since the same value of q₃ occurs at points 63 and 65.At an RF frequency of 5 MHz, the RF amplitude is ramped from a minimumvalue at 66 to a maximum at 67 returning to a minimum at 68. Therelatively flat top shape of the ion signal which occurs between 78 and67 indicates that very efficient ion transmission at m/z 110 isoccurring over a range of RF amplitude or q₃. FIG. 3b shows the iontransmission efficiency for m/z 872 generated simultaneously with thedata shown in FIGS. 3a and 3 c. The quadrupole mass filter was scannedfrom m/z 871.7 to 872.7 while applying the same values of RF frequencyand amplitude as were run for m/z 110 in FIG. 3a. The RF amplitude wasset at 1 MHz with a low amplitude at 69. As the RF amplitude wasincreased from a minimum at 69 to a maximum at 71, the maximum iontransmission occurred at 70. As expected, the maximum ion transmissionoccurs at the same q₃ value when ramping the RF amplitude from itsmaximum value at 71 back to its minimum at 72. When the frequency isincreased to 3 MHz and the RF amplitude ramped from a minimum at 73 to amaximum at 74 back to a minimum at 75, efficient ion transmission isachieved over a wide range of RF amplitude or q₃. FIG. 3c shows the iontransmission efficiency for m/z 1743 (scanned from 1742.5 to 1743.5)over the same RF frequency and amplitude ranges as were used for m/z 110shown in FIG. 3a. FIG. 3 illustrates that for a given backgroundpressure gradient, varying orders of magnitude over the multipole ionguide length, efficient ion transmission through the ion guide operatedin the AC-only mode can be achieved for a broad range of m/z values. Forexample, if the maximum efficiency in ion transmission were desired overthe entire range of m/z tested in FIG. 3 then the RF frequency would beset at 4 MHz and run with an RF amplitude that could fall roughly at theq₃ value indicated at point 76. For this fixed value of q₃ andbackground pressures at which the transmission efficiencies weremeasured, m/z values from less than 110 to over 1743 would beefficiently transmitted through the multipole ion guide. FIG. 4 is amass spectrum of Glucagon taken with the ion guide q₃ value set at thepoint indicated by 76 in FIG. 3. A solution of 2 picomole/μl of Glucagonin 1:1 methanol:water was Electrosprayed using continuous infusionsample introduction in an API/MS instrument as configured in FIG. 2 andthe quadrupole mass spectrometer was scanned from 20 to 1900 m/z. The(M+4H)⁺⁴, (M+3H)⁺³ and (M+2H)⁺² Glucagon peaks are indicated by 80, 81and 82 respectively. The use of a multiple pumping stage multipole ionguide to transmit and focus ions exiting from a free jet expansion intoa mass analyzer allows flexibility in configuring an API/MS instrumentwithout compromising sensitivity. Smaller multiple pumping stage API/MSinstruments can be configured with vacuum pumps chosen to minimizeinstrument cost without compromising performance. Multiple pumping stagemultipole ion guides can be configured and operated to allow efficiention transmission and focusing over a a wide range of pressure gradients.Multipole ion guides can be configured for use with a number of massanalyzer types which may require different operating pressure regimes.For example a quadrupole mass analyzer can operate efficiently at avacuum pressure of 2×10⁻⁵ torr or below whereas a TOF analyzer requiresbackground pressures in the low 10⁻⁷ torr range or lower to avoidsignificant numbers of collisions between ions and background gas duringthe ion flight time. A multiple vacuum pumping stage API/MS instrumentwith a single or a multiple pumping stage multipole ion guide can beconfigured to maximize ion transmission and focusing yet minimizepumping cost.

FIG. 3 illustrates that the a_(n) and q_(n) values can be set so that alow or a high m/z cutoff in ion transmission occurs. For example if theRF frequency were set at 3 MHz and the RF amplitude operated anywherefrom point 79 to 62 then ions with m/z 110 or lower would not betransmitted through the multipole ion guide to the mass analyzer.Similarly, if the RF frequency were operated at 7 MHz with the RFamplitude set at the value indicated by 77 then a high m/z cutoff in iontransmission through the ion guide to the mass analyzer would occur.FIGS. 5a and 5 b illustrate operation of the multipole ion guide 40 withthe q_(n) value set for passing a broad range of m/z and the q_(n) valueset at a point where a low m/z transmission cutoff occurs. FIG. 5a is amass spectrum taken from electrospraying a solution of 2 picomole/μl ofArginine in 1:1 methanol:water using continuous infusion with themultipole ion guide 40 q₃ value set to transmit a wide range of m/zvalues. The cation impurities of sodium 85 (m/z 23) and potassium 86(m/z 39) present in solution appear in the mass spectrum as well as theprotonated methanol monomer 87 (m/z 33) and dimer 88 (m/z 65) and thesample Arginine protonated peak 90 at m/z 175. FIG. 5b shows a massspectrum taken with the same solution being Electrosprayed underidentical spray conditions but with the hexapole ion guide q₃ value wasset so that a low m/z cutoff occurs. Ion transmission below 100 to 120m/z has been effectively cut off without reducing the ion transmissionefficiency of Arginine 91 or higher m/z values. Another example of thisis illustrated in FIGS. 6a and 6 b where a 2 picomole/μl sample ofGramicidin S in 1:1 methanol:water was Electrosprayed with continuousinfusion using the API/MS configuration illustrated in FIG. 2. In FIG.6a the hexapole 40 q₃ value is set to transmit a wide m/z range and animpurity potassium peak 92 and the protonated doubly charged GramicidinS peak 93 (M+2H)⁺² are observed in the mass spectrum. FIG. 6b is a massspectrum of the same Gramicidin S solution Electrosprayed usingidentical conditions as in FIG. 6a but with the hexapole 40 q₃ value isset so that a low m/z cutoff occurs. The potassium ions are no longertransmitted to the mass analyzer but the ion transmission efficiency ofthe doubly charged Gramicidin S ions as shown by peak 94, is stillretained. A q_(n) value can also be selected to cause a high m/z cutoffas illustrated in FIGS. 7a and 7 b where a mixture of Arginine, LeucineEnkephalin and Gramicidin S, 2 picomole/ul each in 1:1 methanol:waterwas Electrosprayed using the API/MS configuration shown in FIG. 2. FIG.7a is a mass spectrum taken where the multipole ion guide 40 q₃ valuewas set to transmit a wide range of m/z values. The Arginine (M+H)⁺ peak95, Leucine Encephalon (M+H)⁺ peak 96 and doubly charged Gramicidin S(M+2H)⁺² peak 97 are present in the mass spectrum as well as the lowerm/z ion peaks 98. FIG. 3b is a mass spectrum taken where the samesolution is Electrosprayed using identical spray conditions except thatthe ion guide 40 q₃ value has been set so that the lower m/z ions aretransmitted as indicated by peaks 99 but the higher m/z ions are nottransmitted through the multipole ion guide 40.

A valuable feature of multipole ion guides when operated in higherbackground pressures is that ions traversing the length of the ion guideexperience a number of collisions with the background gas resulting inthe cooling of the ion kinetic energy. As the ions enter the multipoleion guide and are transmitted through it, the RF or combined RF-DC fieldeffectively traps the ions from dispersing in the radial direction dueto collisions with the background gas yet permits movement of ions inthe axial direction often driven by the gas dynamics. Ions whichexperience a number of low energy collisions with the neutral gas withinthe multipole rod assembly have their kinetic energy reduced resultingin a narrowing of the ion energy spread for those ions which exit themultipole rods. The number of collisions an ion experiences as ittravels the length of the ion guide is a function of the rod length andthe background pressure inside the rods. If the relative voltages of thecapillary exit lens 50, ring lens 51, skimmer 47 and the multipole ionguide 40 DC offset potential remain the same then the ions entering themultipole ion guide will have similar energy spreads and will betransmitted to the exit of the multipole ion guide with the sameefficiency. With the relative upstream lens potentials held constantwith the ion guide DC offset potential, the ion kinetic energy coolingdue to collisions will remain consistent as the multipole DC offsetpotential is adjusted. Consequently, with a multipole ion guide operatedin a higher vacuum pressure region where ion collisional cooling occurs,the narrow energy spread of the ions can be maintained independent ofchanges in the mean ion energy when the ion guide DC offset potential isadjusted.

To illustrate this point, the energy spread of a doubly chargedGramicidin S (M+2H)⁺² on (m/z 571) was measured by ramping the voltageof lens 53 in FIG. 2 while monitoring the mass spectrometer ion signal.This technique will not give a precise profile of ion energy becauselens 53 is a focusing element as well as having the ability to applystopping potentials. However, even though the focusing characteristicswill change slightly as the voltage of 53 is ramped, the boundaries ofion energy for a given m/z can be attained. Using the multipole ionguide configuration of FIG. 2 and maintaining background pressure invacuum stage 53 at 2 torr, vacuum stage 41 at 150 millitorr, vacuumstage 42 at 4×10⁻⁴ torr and vacuum stage 54 at 6×10⁻⁶ torr, the mean ionenergy was changed by adjusting the DC offset potential of the hexapolerelative to the quadrupole entrance aperture 47 ground potential. FIGS.8a, b and c show the ion signal of the Gramicidin S protonated doublycharged peak (M+2H)⁺² for three different hexapole ion guide 40 DCoffset potentials. In FIG. 8a the hexapole ion guide 40 was operated inthe AC only mode with the DC offset potential set at 0.1 volt relativeto the quadrupole entrance aperture 47. FIG. 8a shows the ion signallevel 100 at m/z 571.6 for three consecutive voltage ramps of lens 53from 2 to 8.2 volts. Over ninety percent of the m/z 571.6 ions fallwithin a one volt window of ion energy. FIG. 8b shows the ion signal 101at m/z 571.6 for three consecutive voltage ramps of lens 53 from 19 to21.2 volts with the hexapole ion guide 40 DC offset potential set at15.3 volts. Ninety percent of the 571.6 m/z ions detected have an energythat falls within a one volt window. Similarly, FIG. 8c shows the ionsignal 102 at m/z 571.6 for three consecutive voltage ramps of lens 53from 29 to 35 volts with the hexapole ion guide 40 DC offset potentialset at 25.1 volts. Once again, over ninety percent of the m/z 571.6 ionsexiting the hexapole ion guide 40 are within a 1 volt energy window. Themean ion energy ranges from roughly 3 to 5.2 volts higher than the DCoffset potential set on the hexapole ion guide 40 in FIGS. 8a, b and c.Ion acceleration driven by the expanding gas in the free jet occurringin vacuum stage 51 may account for 2.6 to 3 volts of this added ionenergy for Gramicidin S ions. It is not yet certain where the one to twovolts of energy over 3 volts is added as the multipole ion guide DCoffset potential is raised. The efficient transport of ions with lowenergy spread combined with the ability to control the average ionenergy for a given m/z by adjusting the multipole ion guide 40 DC offsetpotential, allows higher sensitivity to be achieved at higher resolutionfor many mass analyzer types.

An API/MS system which incorporates a multipole ion guide with a portionof its length operating in a vacuum pressure which is high enough tocause collisional cooling as ions traverse the rod length allows threesignificant performance features. The first is that the ion guideoperated in the presence of sufficient background collisions can reducethe ion energy spread without reducing ion transmission efficiency whenrun with the proper values of a_(n) and q_(n) set. Second, the mean ionenergy for a given m/z can be adjusted by changing the DC offsetpotential of the multipole ion guide without causing significant changesin ion energy spread. Third, the ion energy can be adjusted by changingthe ion guide DC offset potential without reducing the ion transmissionefficiency through the multipole ion guide. An example to illustratethese three features is given in FIG. 9 which shows a mass spectrum 103of a doubly charged protonated Gramicidin S (M+2H)⁺² peak with partiallyresolved isotope peaks. The spectrum was taken by electrospraying a 2picomole/ul Gramicidin S sample in a 1:1 methanol: water solution usingan API quadrupole mass spectrometer system as configured in FIG. 2. TheDC offset potential of hexapole 40 was set to 0.1 volts relative to theground potential quadrupole entrance aperture 47. With this low ionguide DC offset voltage setting, higher resolution was achievable atcomparable sensitivities than could be attained with the hexapole DCoffset potential set at 15 volts. At lower ion energies, transmissionlosses can occur between the multipole ion guide exit 52 and thequadrupole mass filter 57 depending on the focusing and transfercharacteristics of static voltage lenses 53 and 47 in the presence ofthe multipole ion guide 40 and the quadrupole mass filter 57 fringingfields. The performance tradeoffs between ion energy, resolution andsignal level for the quadrupole mass filter 57 used, favored lowerenergy ions when scanning with higher resolution settings. Using astatic voltage lens system as illustrated in FIG. 1 the resolution andsensitivities shown in FIG. 9 could not be achieved. The use of amultipole ion guide operated with the appropriate a_(n) and q_(n)setting in a region where background pressures are high enough to causecollisional cooling of ions as they traverse the length of the ion guideimproves API/MS system performance when compared with static lensconfigurations having little or no ion kinetic energy cooling.

The performance capabilities of a multipole ion guide operated in abackground pressure region where ion kinetic energy cooling occurs canbe used to improve the performance of different mass spectrometer types.The advantages of improved ion transmission efficiencies when usingmultiple vacuum pumping stage multipole ion guides in conjunction withquadrupole mass analyzers was illustrated with examples given above. Theability to set the mean ion energy by adjusting the multipole DC offsetpotential without changing the narrow energy spread per m/z value can beused to improve the resolution and sensitivity of scanning andnon-dispersion mass analyzers including quadrupole, magnetic sector,TOF, ion trap and FT-ICR mass spectrometers. Higher API/MS systemsensitivities and resolutions can be achieved and pumping costsminimized when multipole ion guides which extend through two or morevacuum pumping stages are used in the initial vacuum pumping stagesbefore the mass analyzer. The ability to operate a multipole ion guidein a mode where a cutoff in ion transmission for a given m/z range isset offers little operational advantage when applied with scanning ordispersion mass analyzers such as magnetic sector or quadrupole massfilters. These dispersion or scanning mass analyzer types transmit ionsonly in a narrow range of m/z at any given time to the detector.However, for mass analyzers which are non dispersion such as TOF, iontraps and FT-ICR which analyze packets of ions, the ability of themultipole ion guides to limit the range of m/z values transmitted intothe mass analyzer can enhance system performance. FIG. 10 is a diagramof a four vacuum pumping stage orthogonal pulsing API/MS system with areflectron Time-Of-Flight mass analyzer. For illustration purposes, anelectrospray ion source is shown as the API source although this couldalternatively be an APCI or an ICP source as well. Sample bearing liquidis introduced through the electrospray needle 110 and is Electrosprayedor nebulization assisted Electrosprayed into chamber 111 as it exits theneedle at 112. The charged droplets produced, evaporate and desorb gasphase ions both in chamber 111 and as they are swept into vacuum throughthe annulus in capillary 113. A portion of the ions that enter the firstvacuum stage 133 through the capillary exit 114 are focused through theorifice 136 in skimmer 116 with the help of lens 115 and the potentialset on the capillary exit 114. Ions passing through skimmer orifice 136enter the multipole ion guide 118. The ion guide 118 begins in vacuumpumping stage 117 and extends unbroken into vacuum stage 119. If themultipole ion guide AC and DC voltages are set to pass ions fallingwithin a range of m/z then ions within that range which enter themultipole ion guide will exit at 121 and are focused with exit lens 120through the TOF analyzer entrance orifice 122. This primary ion beam 134ion beam passes between electrostatic lenses 123 and 124 located in thefourth pumping stage 126. The relative voltages on lenses 123, 124 and125 are pulsed so that a portion of the ion beam 134 falling in betweenlenses 123 and 124 is ejected as a packet through grid lens 125 andaccelerated down flight tube 127. The ions are steered by x and y lenssets diagrammatically illustrated by 128 as they continue their movementdown flight tube 127. In the configuration shown, the ion packet isreflected through a reflectron or ion mirror 130 and detected atdetector 131. As a pulsed ion packet proceeds down flight tube 127, ionswith different m/z separate in space due to their velocity differencesand arrive at the detector at different times. The use of orthogonalpulsing in an API/TOF system helps to reduce the ion energy spread ofthe initial ion packet allowing higher resolution and sensitivity to beachieved.

For a given primary ion beam current passing through the mass analyzeraperture 122, the lower the ion energy, the more ions that will bepresent in the pulsing region per pulse. This has a direct impact on theion signal response that can be achieved per pulse. Also, the lower theprimary ion beam electrostatic energy, the less ion density versus m/zdiscrimination that will occur in pulsing region 135. Thisdiscrimination occurs because the lower m/z ions acceleratedelectrostatically will move faster than the higher m/z ions andconsequently will have less relative density for a similar ion currentper m/z in the pulsing region. A distinction is made here between ionsaccelerated electrostatically and those accelerated due to gas dynamicsin the free jet. Although some slippage occurs for higher molecularmasses, ions accelerated solely by the neutral gas expanding into vacuumin a free jet form an ion beam that is closer to being mono-velocityrather than mono-energetic. Electrostatic acceleration in the absence ofcollisions with background gas will create an ion beam that is closer tobeing mono-energetic. A mono-velocity beam entering pulsing region 135will reduce the differences in ion density versus m/z for a given ionflux and hence allow generation of a mass spectrum whose relative peakheights are more representative of the relative m/z intensities in theoriginal ion beam 134. The translational energy of ions in the primaryion beam 134 will be the sum of the energy imparted by the expanding gasand by electrostatic acceleration. Multipole ion guide 118, a portion ofwhich is operated in a higher pressure vacuum region, can deliver an ionbeam having low translational energy through the mass analyzer orifice122 with minimal beam divergence. When static lens systems are used,lowering of the ion beam energy generally results in increased beamdivergence. Beam divergence will not only reduce the ion beam intensityentering aperture 122 but will also increase the beam cross sectionalarea in pulsing region 135. Primary ion beam divergence can result inreduced resolution in an orthogonal pulsed TOF geometry. Use of themultipole ion guide 118 to aid in delivering ions to the pulsing regioncan reduce the degree of ion beam divergence for lower ion beamenergies. The net result is improved sensitivity and resolution.

The effective inner diameter of multipole ion guide 118 is reduced tominimize the neutral gas conduction between vacuum pumping stages 117and 119 without compromising ion transmission efficiency. The effectiveinner diameter for multipole ion guide 118 is typically 2.5 millimetersor less. The ion guide geometry itself places an upper limit on thecross section of the ion beam exiting at 121. By limiting the ion beamdiameter exiting multipole ion guide 118 to less than 2 mm, aperture 122can be reduced to 2 mm with little or no loss ion transmissionefficiency into pulsing region 135. The smaller the aperture 122 sizethe less neutral gas that will pass into vacuum pumping stage 126,reducing the vacuum pumping speed requirements and lowering instrumentcost. The smaller the primary ion beam 134 which enters pulsing region124, the less spatial spreading which occurs before the ions are pulsedout of region 135 and into flight tube 127. With orthogonal pulsing,reducing the ion beam 134 width can reduce the pulsed ion packet widthor spatial and energy spread, potentially resulting in increased TOFsensitivity and resolution performance.

A narrow ion energy spread is desirable in orthogonal pulsing TOFbecause the orthogonal component of ion energy which is the initial ionbeam energy, translates into sideways movement of ions as they traversethe flight tube. The lower the energy spread in the initial ion beam thetighter the initial m/z ion packet remains in the radial direction as ittravels through flight tube 127 resulting in more ions focused onto thesurface of detector 131. As shown in FIG. 8, operation of a multipoleion guide in a vacuum pressure regime where ion kinetic energy coolingoccurs results in narrowing of the ion energy spread and the ability tolower ion energy without reducing the ion transmission efficiency orincreasing the ion energy spread. The ability to lower ion energy whilemaintaining a low ion energy spread can help to improve the sensitivityand increase the duty cycle of a TOF mass analyzer. Ions of a given m/zand energy will take time to refill the gap between lenses 123 and 124after a pulse has occurred. If the length of the gap is roughly 2 cmthen an ion at m/z 1000 with 20 volts of energy will take 10.2 μsec totravel 2 cm and fill the pulsing space. The same ion at 3 volts ofenergy will take 26.3 μsec to travel 2 cm and fill the pulsing region.Those ions which are not pulsed into the flight tube are lost as theyimpact the walls of pulsing region 134 and are neutralized. If the ionpackets are pulsed at a rate of 10,000 times per second, that is onceevery 100 μsec, then pulsing a 3 volt primary ion beam 134 will improvethe duty cycle and consequently the sensitivity by a factor of 2.6 whencompared with pulsing a primary ion beam 134 having 20 volts oftranslational energy. The ability of a multipole ion guide to deliverion beam 135 with a small cross section and a mean energy of less than 5volts, significantly improves performance of an API/TOF system over thatwhich can be achieved using a static voltage lens system.

The ability of the multipole ion guide to selectively transmit a rangeof m/z values while cutting off the transmission of m/z outside thatrange can be used to increase the duty cycle and detector sensitivity inan API/TOF system. The duty cycle can be increased in TOF by reducingthe range of ion m/z that enters pulsing region 135. Recalling FIGS. 5,6 and 7, the a_(n) and q_(n) values of a multipole ion guide can be setso that the ion guide behaves as a low pass or a high pass filter withm/z transmission cutoff points. If a DC potential is applied to thepoles where each adjacent pole has opposite DC polarity, the a_(n) andq_(n) values can be selected so that the multipole ion guide will pass anarrower range of m/z. Quadrupoles are commonly used in this mode asmass filters in vacuum pressure regimes that are maintained below 2×10⁻⁵torr where the effects due to ion collisions with the background gas arenegligible. When ± DC is imposed on the multipole rods with considerablebackground pressure present, the transmission characteristics of eachtype multipole ion guide or mass filter assembly must tested andqualified. Ion transmission maps of a_(n) and q_(n) may not be the samefor multipole ion guides with different numbers of poles and operated indifferent background pressures. One variable which effects duty cycle ina TOF instrument is the repetition rate at which ions are pulsed in theflight tube, accelerated and detected. Assuming that the pulsing region135 can refill between pulses, that is the primary ion beam 134 energyis set to satisfy this criteria, the pulsing repetition rate will belimited by the fastest flight time of the lowest m/z ion and the slowestflight time of the highest m/z ion in consecutive ion packets travelingthrough flight tube 127 to the detector. Any overlap of ions from onepulsed packet to the next will increase the difficulty in interpretingthe resulting mass spectrum. If ions of lower or higher m/z were not ofinterest in a given analysis, those ions could be preventing fromentering the pulsing region by selecting an appropriate a_(n) and q_(n)value for the multipole rod 118 operation. By reducing the arrival timespread of an ion packet as it travels down the flight tube, the time inbetween pulses can be reduced resulting in an increase in duty cycle.

Consider an example where an API/MS system as diagrammed in FIG. 10 hasan effective ion flight length of 2.5 meters and a flight tube ionacceleration energy of 1500 electron volts (ev). The larger thedifference in arrival times at the TOF detector between close ion m/zvalues, the higher the resolution which is theoretically achievable.However, for continuous ion beam API sources, increasing resolution byincreasing the arrival time spread of ion packets may reduce duty cycle.Relative flight times in a 2.5 meter TOF tube with an ion acceleratingenergy of 1500 ev would be as follows for different values of m/z:

m/z Flight time (μsec) 1 4.6 19 20.3 100 46.5 500 103.9 1000 146.9 2000207.8 3000 254.5 5000 328.6 10000 464.7

Subtracting the slowest from the most rapid flight time of ions presentin the pulsed packet will determine the minimum time required in betweenconsecutive pulses to avoid low m/z ions of the trailing pulse catchingup with high m/z ions of the leading pulse. If m/z ions ranging fromprotonated water (m/z 19) to m/z 3000 are present in the pulse ionpackets, then a delay of 255 μsec must be maintained between consecutivepulses allowing approximately 3,921 pulses per second. A primary ionbeam 134 with ions of m/z of 3000 and lower and with 3 volts oftranslational energy will fill the 2 cm pulsing gap 135 length in lessthan 45 μsec. The longer the delay between pulsing of ions into theflight tube, the lower the duty cycle resulting in lower sensitivity fora given primary ion beam intensity. If the ions of interest for a givenanalysis fell in a narrow m/z window, say below m/z 1000 then themultipole ion guide a_(n) and q_(n) values could be set to pass onlyions below m/z 1000. The minimum time delay between pulses would bereduced to 147 μsec effectively increasing the duty cycle andpotentially sensitivity by a factor of 1.7. Conversely, if the massrange of interest fell above m/z 500 and the m/z values present in theprimary ion beam were below 2000 m/z then the multipole ion guide 118operating a_(n) and q_(n) values could be set to reject ions below 500m/z. The ion packet pulse frequency could be set to over 9500 pulses persecond increasing duty for all m/z values transmitted into pulsingregion 135.

Layered Multichannel Plate (MCP) electron multipliers are often used fordetectors in TOF mass spectrometry. The individual channel recovery timeof an MCP channel after an ion hits and causes an electron cascade canbe as long as 1 millisecond. If an ion hits the channel before it hasrecovered then little or no electron cascade will occur and the ion willremain undetected. Lower m/z ions which arrive at the detector first fora given pulsed ion packet could deaden channels for heavier m/z ionswhich follow. Also if the packet pulse rate exceeds 1000 hertz, that isthe time between pulses is shorter than the MCP channel recovery time,this could result in reduction in signal intensity as ions arriving atthe detector yield reduced secondary electron cascade intensity becauseions from preceding pulses have deadened a number of channels. If theions of interest for a given analysis fall within a limited m/z range,detector response can be increased for ions of interest by preventingunwanted m/z values from reaching the detector. The multipole ion guide118 m/z transmission window can be selected to minimize the number ofunwanted m/z values from entering the pulsing region 135, eliminatingthose m/z values from reaching the detector. Selectively preventing ionsfrom reaching the detector has also been accomplished by deflecting aportion of an ion packet as it traverses the TOF tube before it reachesthe detector. Ion lenses used for deflecting ions are diagrammaticallyrepresented by 132 in FIG. 10. The use of multipole lens to limit m/zvalues from entering the TOF pulsing region is a complimentary techniqueto using deflectors in the flight tube. Deflecting lenses, however, willnot aid increasing duty cycle unless they are employed very early in theion flight path, a region where m/z separation may be poor. A linearpulsed API/MS system as reported by Boyle, Whitehouse and Fenn (RapidCommunications in Mass Spectrom. Vol. 5, 400-405, 1991) would have asimilar increase in sensitivity and duty cycle by incorporation of amultipole ion guide into the upstream vacuum stages as is achieved inorthogonal pulsing TOF configurations.

When API sources are interfaced with ion traps and FT-ICR massanalyzers, the use of multipole ion guides in the vacuum transfer opticscan be used to improve performance by increasing ion transmissionefficiency into the mass analyzer trapping region, lower the ion energyspread and reducing space charge limits for desired m/z ranges byselectively transmitting limited m/z ranges. FIG. 11 diagrams a threevacuum pumping stage API/ion trap system where a multipole ion guidebegins in vacuum pumping stage 148 and extends continuously through thethree vacuum pumping stages. An electrospray or nebulizer assistedelectrospray ion source is shown interfaced to ion trap massspectrometer 154. Sample bearing liquid is introduced into theelectrospray needle entrance 140 and is Electrosprayed or nebulizerassisted Electrosprayed as it emerges from the electrospray needle tip141. The charge liquid droplets produced in the electrospray chamber 142drift toward the capillary entrance 144 against a flow of countercurrentdrying gas 164. Ions are produced from the evaporating charged dropletsand are swept into vacuum through capillary 145. This capillary may beheated by capillary heater 146 which aids in heating the gas expandingthrough the capillary into vacuum. Ions exiting the capillary at 147 areaccelerated into the first vacuum pumping stage 148 by the neutral gasfree jet expansion. A large portion of ions exiting the capillary enterthe multipole ion guide 165 and are effectively trapped and efficientlytransported through its entire length. The ions exit multipole ion guide165 in the third vacuum stage 151 and are focused into the ion trap 154through the its endplate 155 by lens 162. The pressure in vacuum stage148 can range from 0.5 to 2 torr depending on the capillary 145 innerdiameter and length, the vacuum pump size chosen and the temperature atwhich the capillary heater is run. The third pumping stage 151 isusually maintained at a pressure below 5×10⁻⁵ torr to insure properfunctioning of the electron multiplier detector 152, however, theinternal trap pressure is often set higher than the background pressurein stage 151 by the addition of helium directly into trap 154. Thepressure in pumping stage 157 is generally maintained at a pressure lessthan 150 millitorr.

The multipole ion guide 165 has rods or poles 150 which begin in pumpingstage 148, continue unbroken through pumping stage 157 and extend intopumping stage 151. Insulators and mounting brackets 156 and 158 servethe dual purpose of supporting the multipole rod assembly andpartitioning the vacuum chambers to minimize the flow of background gasinto downstream pumping stages. FIG. 12 illustrates a cross section of ahexapole assembly taken at insulator 156. The six rods 160 are held inan equally spaced position and equal radial distance from the centerlineby attachment to insulator 156. The insulator is configured to minimizethe effective cross sectional area of the internal opening withoutdistorting the electrostatic field produced by the hexapole rods duringoperation inside multipole rod assembly cross section area 161. Roddiameters as small as 0.5 mm have been constructed with an inner rodspacing 166 of 2 mm to minimize neutral gas conductance into downstreampumping stages and reduce the size and cost of vacuum pumps required.Increasing the length of insulators 156 and 158 also helps to reduce theneutral gas conductance. The smaller the ion guide assembly internalcross section area 161 with proportionally small rod 160 diameters, thesmaller the ion beam cross section which exits the multipole ion guide.The smaller the ion beam cross section which is transmitted through amultipole ion guide 165 and exit lens 162, the smaller the effectiveaperture size which is required in ion trap end plate 155.

The multipole ion guide 165 can efficiently transport ions throughgradient in background gas pressure. As was shown in FIGS. 8a, b and c,the ion energy spread is reduced due to ion collisional cooling with thebackground gas. Higher trapping efficiency can be achieved with ionsentering ion trap 154 when the ions have a narrow energy spread.Increased trapping efficiencies result in higher signal sensitivity fora given ion current entering trap 154. The ability to selectivity cutoffa range of m/z transmission through multipole ion guide 165 can also beused to increase sensitivity in ion trap mass spectrometers. Ion trapsmust first trap ions and then conduct a mass analysis on a packet oftrapped ions. The trap can only hold a limited number of ions before itsuffers from space charge effects which can shift measured m/z valuesand deteriorate resolution. For a given analysis, the multipole ionguide a_(n) and q_(n) value can be set to reduce the m/z range of ionswhich are transmitted to ion trap 154 through exit lens 162 and ion trapendplate 155. This extends the dynamic range signal response for the m/zvalues of interest by reducing the effects of space charging from m/zvalues which are not of interest for a given analysis. For example, thecontamination 85, 86 and solvent related peaks 87, 88 observed in thespectrum of FIG. 5a would fill up the trap with charge and reduce thesignal intensity range over which the Arginine peak 90 could be observedin the ion trap because the lower m/z peaks would be largely responsiblefor the space charge limits being reached in the ion trap. If themultipole ion guide a_(n) and q_(n) value were set for a low m/z cutoffas shown in the spectrum of FIG. 5b then the Arginine peak 91 would bethe primary source of ions entering the trap and consequently the signalto noise observed would have a higher dynamic range before the effectsof space charging would be observed. Increased dynamic range within aspectrum is important for trace analysis and analysis where accuraterelative peak heights are needed to determine relative concentrations insolution.

FT-ICR mass spectrometers also trap ions and conduct mass analysis withpackets of ions. Similar to ion traps, improvements in performance withan API/FT-ICR MS instrument can be achieved by using a multipole ionguide operated in vacuum pressure were ion kinetic energy cooling occursreducing the ion energy spread for a given m/z. Effects due to spacecharge limits in the FT-ICR MS trapping cell can be reduced in a similarmanner as described for ion traps above effectively increasing thedynamic range of the FT-ICR MS for m/z values of interest in a givenanalysis. The smaller effective inner diameter of these multipole ionguides produces a small ion beam cross section allowing a reduction inthe aperture sizes leading to the FT-ICR mass analyzer withoutsignificantly reducing ion transmission through the smaller orifices.

Various configurations of hybrid API/mass spectrometers have beenreported whose performance would be enhanced by the incorporation of amultipole ion guide in the vacuum ion transport region. Chien, Michaeland Ludman (Anal. Chem., vol. 65, 1916-1924, 1993) have used an ion trapto trap ions entering from an API source and pulse them into a TOF massspectrometer flight tube. A multipole ion guide could be effectivelyemployed in the upstream vacuum stages to transmit ions from the higherpressure vacuum regions into the ion trap of this API/ion trap/TOFinstrument.

Each mass spectrometer type has its own ion energy, entrance optics andvacuum requirements. The configuration of multipole ion guides,particularly those that extend through two or more vacuum pumping stagescan be geometrically and operationally tailored to the instrument inwhich they are incorporated. However, single pumping stage multipole ionguides can be used effectively as well with less constraint imposed onthe geometry of the ion guide to limit neutral gas conduction along itslength. Two variations for configuring multipole ion guides in API/MSTOF and ion trap systems are shown in FIGS. 13 and 14. FIG. 13 is adiagram representation of a 3 vacuum stage API/ion trap massspectrometer system where a multipole ion guide 170 is located in vacuumpumping stage 172. Ions passing from pumping stage 171 through skimmerorifice 176 are trapped from moving to far off axis in the radialdirection and transmitted through ion guide 170. The ions exiting ionguide 170 are focused by exit lens 175 into ion trap 177 throughendplate 174. The ion trap endplate aperture 178, also serves as theorifice into the third vacuum pumping stage 173. Ions can be injectedinto an ion trap through different gaps or apertures in the ion trapelectrodes, however, this configuration is shown as one embodiment. Thevacuum pressure in vacuum stage 172 and the multipole ion guide 170length can be configured to cause sufficient ion collisional coolingwith the background neutral gas resulting in a narrowing of ion energyspread for a given m/z. Use of a single pumping stage multipole ionguide may not allow the optimal tradeoffs in performance increase andvacuum pumping cost reduction as is possible with a continuous multiplepumping stage multipole ion guide but some performance advantages can berealized when compared to using a static voltage lens configuration.

Another variation with the use of multipole ion guides is theincorporation of two or more ion guides in consecutive vacuum pumpingstages. This allows different a_(n) and q_(n) values to be set per ionguide but increases system complexity and cost. FIG. 14 is a diagram ofa four vacuum stage API/TOF mass spectrometer system with single vacuumpumping stage multipole ion guides 180 and 181 located in pumping stages184 and 185 respectively. Ions in vacuum stage 183 pass through skimmer190 and enter ion guide 180. The ions which are transported throughvacuum stage 184 by ion guide 180 are focused through the aperture 194by multipole 180 exit lens 187. The ions then enter the a second ionguide 181 in vacuum stage 185 and are focused by lens 188 throughaperture 189 as they exit the multipole ion guide 181. Ions passingthough aperture 189 into vacuum stage 186 are pulsed orthogonally withlens set 191 into the TOF mass analyzer 192. The multipole ion guidescan be operated with independent values of a_(n) and q_(n) may be set tooptimize the TOF duty cycle and sensitivity. Similar to the continuousmultiple pumping stage multipole ion guide configuration, the dualmultipole ion guide configuration as diagrammed in FIG. 14 can be usedreduce the ion energy spread and deliver low energy ions into the massanalyzer. However, with the dual multipole ion guide configuration,losses in ion transmission efficiency may occur in the region of staticvoltage lenses 187 and 195 between the two multipole assemblies 180 and181.

We claim:
 1. An apparatus used for analyzing chemical speciescomprising: a. an ion source operated at or near atmospheric pressurewhich produces ions from solution and delivers said ions into a firstvacuum pumping stage through an orifice; b. two or more vacuum pumpingstages with means for pumping away gas in each vacuum stage whereby eachsuccessive vacuum pumping stage has a lower background pressure than theprevious pumping stage; c. a mass analyzer and detector located in oneor more of the vacuum pumping stages; d. a multipole ion guide whichbegins in one vacuum pumping stage and extends contiguously into one ormore subsequent vacuum pumping stages. Said multipole ion guideconsisting of a multiple of equally spaced parallel poles extending thelength of said ion guide. Said multipole ion guide is positioned in saidvacuum pumping stages to guide ions delivered from said ion sourcethrough a portion of said vacuum stages;. e. a means for applying AC andDC voltages to said poles of said multipole ion guide. f. a means forcontrolling the AC frequency and said AC and DC voltages applied to saidpoles of said multipole ion guide;
 2. An apparatus according to claim 1where said ion source is an electrospray ion source.
 3. An apparatusaccording to claim 1 where said ion source is an Atmospheric PressureChemical Ionization source.
 4. An apparatus according to claim 1 wheresaid ion source is an Inductively Coupled Plasma ion source.
 5. Anapparatus according to claim 1 where said multipole ion guide is ahexapole.
 6. An apparatus according to claim 1 where said multipole ionguide is a quadrupole.
 7. An apparatus according to claim 1 where saidmultipole ion guide has more than six poles.
 8. An apparatus accordingto claim 1 where said mass analyzer is a quadrupole mass filter.
 9. Anapparatus according to claim 1 where said mass analyzer is a magneticsector mass spectrometer.
 10. An apparatus according to claim 1 wheresaid mass analyzer is a Time-Of-Flight mass spectrometer.
 11. Anapparatus according to claim 1 where said mass analyzer is orthogonalpulsing Time-Of-Flight mass spectrometer.
 12. An apparatus according toclaim 1 where said mass analyzer is a hybrid ion trap Time-of Flightmass analyzer.
 13. An apparatus according to claim 1 where said massanalyzer is an ion trap mass spectrometer.
 14. An apparatus according toclaim 1 where said mass analyzer is a Fourier Transform massspectrometer.
 15. An apparatus according to claim 1 which includes threeof said vacuum pumping stages.
 16. An apparatus according to claim 15where said multipole ion guide begins in vacuum stage one and extendscontiguously from said vacuum pumping stage two.
 17. An apparatusaccording to claim 15 where said multipole ion guide begins in vacuumstage two and extends contiguously into said vacuum pumping stage three.18. An apparatus according to claim 1 which includes four of said vacuumpumping stages.
 19. An apparatus according to claim 1 which includesmore than four of said vacuum pumping stages.
 20. An apparatus accordingto claim 1 where said ion guide extends continuously from one vacuumpumping stage into the next of said vacuum pumping stages.